Supplementary Material for: The association of glaucoma with ischemic stroke and functional outcome after ischemic stroke from the perspective of causality

Introduction: Glaucoma may be related to ischemic stroke (IS) and poor outcomes after IS in observational studies, while the causal association remains unclear. Methods: We obtained single nucleotide polymorphisms (SNPs) related to glaucoma from the gene-wide association study (GWAS) conducted by the FinnGen consortium. The GWAS included a total of 13,614 cases and 295,540 controls. The summary-level of datasets regarding IS were collected from the MEGASTROKE consortium, including 34,217 cases and 406,111 controls. Furthermore, we acquired summary statistics datasets for functional outcomes following IS from the GWAS meta-analysis conducted by the GISCOME consortium, which involved 6,021 individuals. The genetic association estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Score (mRS), including 3,741 cases with good functional outcomes (mRS=0-2) and 2,280 subjects with poor functional outcomes post-stroke (mRS=3-6). Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. Results: Genetically, glaucoma is associated with an increased risk of IS (odds ratio [OR]=1.08, 95% confidence interval [CI] = 1.02-1.14, P = 0.0039), as well as poor prognosis after IS with adjustment for severity (OR=1.64; 95% CI=1.27-2.13, P=0.0001) and functional outcome after IS (OR=1.45, 95% CI=1.12-1.87, P=0.0038). Through sensitivity analyses, we confirmed the robustness of the results. In addition, we did not identify any causal association between IS, functional outcome after IS, and glaucoma in reverse analysis. Conclusion: Our study provides evidence suggesting a potential genetic causal relationship between glaucoma and an increased risk of IS, as well as a poor functional outcome following IS. Future studies are necessary to confirm these findings

Supplementary Material for: The association of glaucoma with ischemic stroke and functional outcome after ischemic stroke from the perspective of causality

Introduction: Glaucoma may be related to ischemic stroke (IS) and poor outcomes after IS in observational studies, while the causal association remains unclear. Methods: We obtained single nucleotide polymorphisms (SNPs) related to glaucoma from the gene-wide association study (GWAS) conducted by the FinnGen consortium. The GWAS included a total of 13,614 cases and 295,540 controls. The summary-level of datasets regarding IS were collected from the MEGASTROKE consortium, including 34,217 cases and 406,111 controls. Furthermore, we acquired summary statistics datasets for functional outcomes following IS from the GWAS meta-analysis conducted by the GISCOME consortium, which involved 6,021 individuals. The genetic association estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Score (mRS), including 3,741 cases with good functional outcomes (mRS=0-2) and 2,280 subjects with poor functional outcomes post-stroke (mRS=3-6). Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. Results: Genetically, glaucoma is associated with an increased risk of IS (odds ratio [OR]=1.08, 95% confidence interval [CI] = 1.02-1.14, P = 0.0039), as well as poor prognosis after IS with adjustment for severity (OR=1.64; 95% CI=1.27-2.13, P=0.0001) and functional outcome after IS (OR=1.45, 95% CI=1.12-1.87, P=0.0038). Through sensitivity analyses, we confirmed the robustness of the results. In addition, we did not identify any causal association between IS, functional outcome after IS, and glaucoma in reverse analysis. Conclusion: Our study provides evidence suggesting a potential genetic causal relationship between glaucoma and an increased risk of IS, as well as a poor functional outcome following IS. Future studies are necessary to confirm these findings

Supplementary Material for: Endotoxin Tolerance Inhibits Lyn and c-Src Phosphorylation and Association with Toll-Like Receptor 4 but Increases Expression and Activity of Protein Phosphatases

Endotoxin tolerance protects the host by limiting excessive 'cytokine storm' during sepsis, but compromises the ability to counteract infections in septic shock survivors. It reprograms Toll-like receptor (TLR) 4 responses by attenuating the expression of proinflammatory cytokines without suppressing anti-inflammatory and antimicrobial mediators, but the mechanisms of reprogramming remain unclear. In this study, we demonstrate that the induction of endotoxin tolerance in human monocytes, THP-1 and MonoMac-6 cells inhibited lipopolysaccharide (LPS)-mediated phosphorylation of Lyn, c-Src and their recruitment to TLR4, but increased total protein phosphatase (PP) activity and the expression of protein tyrosine phosphatase (PTP) 1B, PP2A, PTP nonreceptor type (PTPN) 22 and mitogen-activated protein kinase phosphatase (MKP)-1. Chemical PP inhibitors, okadaic acid, dephostatin and cantharidic acid markedly decreased or completely abolished LPS tolerance, indicating the importance of phosphatases in endotoxin tolerization. Overexpression of PTPN22 decreased LPS-mediated nuclear factor (NF)-κB activation, p38 phosphorylation and CXCL8 gene expression, while PTPN22 ablation upregulated LPS-induced p65 NF-κB and p38 phosphorylation and the expression of TNF-a and pro-IL-1ß mRNA, indicating PTPN22 as an inhibitor of TLR4 signaling. Thus, LPS tolerance interferes with TLR4 signaling by inhibiting Lyn and c-Src phosphorylation and their recruitment to TLR4, while increasing the phosphatase activity and expression of PP2A, PTPN22, PTP1B and MKP1

Supplementary Material for: LncRNA HANR Promotes Tumorigenesis and Increase of Chemoresistance in Hepatocellular Carcinoma

<p><b><i>Background/Aims:</i></b> Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death. Critical roles for long non-coding RNAs (lncRNAs) have recently been demonstrated for a variety of cancers, including hepatocellular carcinoma. However, the effect and mechanism of lncRNAs in HCC tumorigenesis and chemoresistance have not been extensively characterized. <b><i>Methods:</i></b> In the current study, we have identified a HCC-expressed lncRNA termed as <i>HANR</i> (HCC associated long non-coding RNA). We identified <i>HANR</i> by microarray analysis and validated its up-regulated expression by quantitative PCR. RNA pull-down and pathway analyses were conducted to evaluate physical and functional interactions with <i>HANR</i>. <i>In vivo</i> experiments were performed to assess tumorigenesis and increase of chemoresistance. In addition, the <i>HANR</i> expression in HCC specimens was detected by FISH. Xenograft and orthotopic mice model was constructed to observe the effect of <i>HANR</i> on tumorigenesis and chemoresistance <i>in vivo</i>. <b><i>Results:</i></b> <i>HANR</i> was demonstrated to be up-regulated in HCC patients and HCC cell lines. Increased <i>HANR</i> expression in HCC predicted short survival of patients. Knock-down of <i>HANR</i> markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin, while over-expression of <i>HANR</i> showed the opposite effects. It was found that <i>HANR</i> bind to GSKIP for regulating the phosphorylation of GSK3β in HCC. <b><i>Conclusion:</i></b> Our results demonstrate that <i>HANR</i> contributes to the development of HCC and is a promising therapeutic target for chemosensitization of HCC cells to doxorubicin, which may represent a promising therapeutic target in the future.</p

Supplementary Material for: General Anesthesia may have Similar Outcomes with Conscious Sedation in Thrombectomy Patients with Acute Ischemic Stroke: A Real-World Registry in China

<b><i>Background and Purpose:</i></b> Clinical trials showed that anesthesia may not influence the functional outcome in stroke patients with endovascular therapy; however, data are lacking in China. Using real-world registry data, our study aims to compare the effects of general anesthesia or conscious sedation on functional outcomes in stroke patients treated with thrombectomy in China. <b><i>Methods:</i></b> Consecutive patients with acute anterior circulation stroke receiving thrombectomy in 21 stroke centers between January 2014 and June 2016 were included in this study. The propensity score analysis with 1: 1 ratio was used to match the baseline variables between patients with general anesthesia and the conscious sedation. The 90-day modified Rankin Scale (mRS), symptomatic intracranial hemorrhage (sICH), and death were compared between groups. <b><i>Results:</i></b> Of the 698 patients undergoing endovascular treatment, 138 were treated with general anesthesia and 560 with conscious sedation. After propensity score matching, 114 general anesthesia and 114 conscious sedation patients were matched. The proportions of patients with 90-day mRS 0–2 were not significantly different between general anesthesia and conscious sedation groups (41.2% [47/114] vs. 46.5% [53/114], <i>p</i> = 0.470), nor were the rates of sICH (21.9% [25/114] vs. 12.3% [14/114], <i>p</i> = 0.072) and 90-day mortality (31.6% [36/114] vs. 21.9% [25/114], <i>p</i> = 0.145). <b><i>Conclusion:</i></b> Anesthesia patterns may have no significant impacts on clinical outcomes in patients with acute anterior circulation occlusion stroke undergoing endovascular treatment in the real-world practice in China

Supplementray Material for: Clinical Effectiveness and Safety Outcomes of Endovascular Treatment for Acute Anterior Circulation Ischemic Stroke in China

<strong><em>Backgrounds and Purpose:</em></strong> This study was aimed at investigating the outcomes and predictors for the poor functional outcome after endovascular treatment (EVT) in a large, mostly Asian population. <b><i>Methods:</i></b> Between January 2014 and June 2016, acute stroke patients with anterior circulation occlusion and EVT were retrospectively enrolled from 21 stroke centers in China. The main outcomes were modified Rankin Scale (0-2 as functional independence, 3-6 as poor) at 90 days, symptomatic intracranial hemorrhage (sICH) at 72 h, and death at 90 days. Logistic regression was used to identify predictors for poor functional outcome at 90 days. <b><i>Results:</i></b> Of the 698 patients, 304 (43.6%) patients had functional independence at 90 days. The sICH rate was 15.5% (108/698) and mortality rate at 90 days was 25.4% (177/698). Age (OR 1.04, 95% CI 1.02-1.07), National Institutes of Health Stroke Scale score at admission (11-20 vs. ≤10, OR 2.38, 95% CI 1.23-4.59; ≥21 vs. ≤10, OR 3.66, 95% CI 1.72-7.80), baseline<b> </b>glucose level (OR 1.09, 95% CI 1.01-1.18), onset to groin puncture >6 h (OR 1.88, 95% CI 1.06-3.31), sICH (OR 15.49, 95% CI 5.16-46.43), and pneumonia (OR 3.15, 95% CI 1.86-5.32) were independent predictors of poor functional outcomes, while good recanalization (OR 0.26, 95% CI 0.13-0.54), preoperative Alberta Stroke Program Early CT Score 8-10 (OR 0.48, 95% CI 0.28-0.83), and good collateral flow (OR 0.50, 95% CI 0.32-0.79) were protective factors. <b><i>Conclusions:</i></b> This study provides evidence in real world to support the performance of EVT in acute anterior circulation stroke patients in Chinese population. Patients with small infarct core, successful recanalization, good collateral status, and short treatment delay without sICH or pneumonia may benefit from EVT